Additives enhancing topical actions of therapeutic agents

ABSTRACT

Composition and method for enhancing therapeutic effects of topically applied agents are disclosed. The cosmetic or therapeutic composition may include one or more of cosmetic or pharmaceutical agents present in a total amount of from 0.01 to 40 percent and one or more of hydroxycarboxylic acids or related compounds present in a total amount of from 0.01 to 99 percent by weight of the total composition. The cosmetic and pharmaceutical agents may include but not limited to age spots, wrinkles and keratoses removing agents; vitamins; aloes; sun screens; tanning, depigmenting and shampooing agents; antiyeasts; antifungal, antibacterial and antiviral agents; topical bronchial dilators and topical cardiovascular agents; hormonal agents; vasodilators; retinoids and other dermatological agents. The hydroxycarboxylic acids and related compounds include organic alpha and beta hydroxycarboxylic acids, alpha and beta ketocarboxylic acids and salts thereof. Topical application of the cosmetic or therapeutic composition has been found to achieve a substantial increase in cosmetic or therapeutic effect of the active ingredient in humans and domesticated animals.

[0001] This invention relates generally to method and compositioncontaining hydroxyacid or related compound for enhancing therapeuticeffects of cosmetic or pharmaceutical agent. As will be subsequentlydescribed in detail, we initially discovered that alpha hydroxy or ketoacids and their derivatives were effective in the topical treatment ofdisease conditions such as dry skin, ichthyosis, eczema, palmar andplantar hyperkeratoses, dandruff, acne and warts.

[0002] We have now discovered that hydroxyacids or related compoundswherein incorporated into a therapeutic composition can substantiallyenhance topical effects of cosmetic and pharmaceutical agents.

[0003] In our prior U.S. Pat. No. 3,879,537 entitled “Treatment ofIchthyosiform Dermatoes” we described and claimed the use of certainalpha hydroxy acids, alpha keto acids and related compounds for topicaltreatment of fish-scale like ichthyotic conditions in humans. In ourU.S. Pat. No. 3,920,835 entitled “Treatment of Disturbed Keratinization”we described and claimed the use of these certain alpha hydroxy acids,alpha keto acids and their derivatives for topical treatment ofdandruff, acne, and palmar and plantar hyperkeratosis.

[0004] In our prior U.S. Pat. No. 4,105,783 entitled “Treatment of DrySkin: we described and claimed the use of alpha hydroxy acids, alphaketo acids and their derivatives for topical treatment of dry skin. Inour recent U.S. Pat. No. 4,246,261 entitled “Additives Enhancing TopicalCorticosteroid Action” we described and claimed that alpha hydroxyacids, alpha keto acids and their derivatives, in small amounts couldgreatly enhance the therapeutic efficacy of corticosteroids in topicaltreatment of psoriasis, eczema, seborrheic dermatitis and otherinflammatory skin conditions.

[0005] In our more recent U.S. Pat. No. 4,363,815 entitled “AlphaHydroxy acids, Alpha Keto acids and Their Use in Treating SkinConditions: we described and claimed that alpha hydroxy acids and alphaketo acids related to or originating from amino acids, whether or notfound in proteins, were effective in topical treatment of skin disordersassociated with disturbed keratinization or inflammation. These skindisorders include dry skin, ichthyosis, palmar and plantarhyperkeratosis, dandruff, Darier's disease, lichen simplex chronicus,keratoses, acne, psoriasis, eczema, pruritus and possibly warts andherpes.

[0006] In our most recent U.S. Pat. No. 4,518,789 entitled “PhenylAlpha-Acyloxyacetamide Derivatives and Their Therapeutic Use” wedescribed and claimed that phenyl alpha acyloxyacetamide derivatives intopical or systemic administration were useful and effective forpruritus, atopic dermatitis, eczema, psoriasis, acne, dry skin,dandruff, malodors of integumental areas, various aches, pains anddiscomforts of skin, joints and other body parts in humans and domesticanimals.

[0007] The intact skin of humans is a very effective barrier to manynatural and synthetic substances. Cosmetic and pharmaceutical agents maybe pharmacologically effective by systemic administration, but many ofthem are much less or totally ineffective on topical application to theskin. Topical effectiveness of a pharmaceutical agent depends on twomajor factors a) Percutaneous absorption and penetration b)Bioavailability of the penetrated pharmaceutical agent to the targetsite in the skin. To be therapeutically effective as a topical agent apharmaceutical drug must penetrate the stratum corneum into theepidermal layers, distributed and bioavailable to the target sites forpharmacologic action. Many pharmacologic agents can readily penetratethe skin but they are not bioavailable to the target sites in the skin,therefore therapeutic effect is minimal and ineffective.

[0008] It has now been discovered that hydroxyacids and relatedcompounds including those described or not described in our previouspatents and additional compounds can substantially enhance thetherapeutic efficacy of cosmetic and pharmaceutical agents in topicaltreatment of cosmetic conditions, dermatologic disorders or otherafflictions. Cosmetic and pharmaceutical agents may include any chemicalsubstances natural or synthetic, intended for topical application to theskin or its appendages in human and animals. Some examples of cosmeticand pharmaceutical agents include age spots and keratoses removingagents, analgesics, anesthetics, antiacne agents, antibacterials,antiyeast agents, antifungal agents, antiviral agents, antiburn agents,antidandruff agents, antidermatitis agents, antipruritic agents,antiperspirants, antiinflammatory agents, antihyperkeratolytic agents,antidryskin agents, antipsoriatic agents, antiseborrheic agents,astringents, softeners, emollient agents, coal tar, bath oils, sulfur,rinse conditioners, foot care agents, fungicides, hair growth promoters,hair removers, keratolytic agents, moisturizer agents, powder, shampoos,skin bleaches, skin protectants, soaps, cleansers, antiaging agents,sunscreen agents, wart removers, wet dressings, vitamins, tanningagents, topical antihistamin agents, hormones, vasodilators, retinoids,bronchial dilators, topical cardiovascular agents and otherdermatologicals.

[0009] The enhancing compounds of the instant invention arehydroxycarboxylic acids and related compounds. There are three groups ofsuch hydroxyacids. The first is hydroxymonocarboxylic acids having thefollowing chemical structure:

R₁(CR₂OH)_(m)(CH₂)_(n)COOH

[0010] wherein

[0011] R₁, R₂=H, alkyl, aralkyl or aryl group of saturated orunsaturated, straight or branched chain or cyclic form, having 1 to 25carbon atoms.

[0012] m=1, 2, 3, 4, 5, 6, 7, 8 or 9

[0013] n=0 or a numerical number up to 23

[0014] When n=0 and m=1 or more, the hydroxymonocarboxylic acid is alsocalled aldonic acid. The name comes from a carbohydrate, aldose, whichmay be oxidized to aldonic acid by the oxidation of the aldehyde groupin aldose to the carboyxlic group.

[0015] The hydroxymonocarboxylic acid may be present as a free acid,lactone, or salt form. The lactone form could be either inter orintramolecular lactone, however, most common ones are intramolecularlactones with a ring structure formed by elimination of one or morewater molecules between a hydroxy group and the carboxylic group. Sincethe hydroxymonocarboxylic acids are organic in nature, they may form asalt or a complex with an inorganic or organic base such as ammoniumhydroxide, sodium or potassium hydroxide, or triethanolamine.

[0016] The hydroxymonocarboxylic acid and its related compounds may alsoexist as stereoisomers such as D, L, and DL forms.

[0017] The typical alkyl, aralkyl and aryl groups for R₁ and R₂ includemethyl, ethyl, propyl, isopropyl, benzyl and phenyl. The hydrogen atomsof the R₁ and R₂ and (CH₂)_(n) may be substituted by a nonfunctionalelement such as F, Cl, Br, I, S or a radical such as a lower alkyl oralkoxy, saturated or unsaturated, having 1 to 9 carbon atoms.Representative hydroxymonocarboxylic acids are listed below:

[0018] 1. 2-Hydroxyacetic acid (Glycolic acid)

[0019] R₁=H, R₂=H, m=1, n=0

[0020] 2. 2-Hydroxypropanoic acid (Lactic acid)

[0021] R₁=CH₃, R₂=H, m=1, n=0

[0022] 3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid)

[0023] R₁=CH₃, R₂=CH₃, m=1, n=0

[0024] 4. 2-Hydroxybutanoic acid

[0025] R₁=C₂H₅, R₂=H, m=1, n=0

[0026] 5. Phenyl 2-hydroxyacetic acid (Mandelic acid)

[0027] R₁=C₆H₅, R₂=H, m=1, n=0

[0028] 6. Phenyl 2-methyl 2-hydroxyacetic acid (Atrolactic acid)

[0029] R₁=C₆H₅, R₂=CH₃, m=1, n=0

[0030] 7. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid)

[0031] R₁=C₆H₅, R₂=H, m=1, n=1

[0032] 8. 2,3-Dihydroxypropanoic acid (Glyceric acid)

[0033] R₁=H, R₂=H, m=2, n=0

[0034] 9. 2,3,4-Trihydroxybutanoic acid

[0035] R₁=H, R₂=H, m=3, n=0

[0036] 10. 2,3,4,5-Tetrahydroxypentanoic acid

[0037] R₁=H, R₂=H, m=4, n=0

[0038] 11. 2,3,4,5,6-Pentahydroxyhenxanoic acid

[0039] R₁=H, R₂=H, m=5, n=0

[0040] 12. 2-Hydroxydodecanoic acid (alpha hydroxylauric acid)

[0041] R₁=C₁₀H₂₁, R₂=H, m=1, n=0

[0042] 13. 2,3,4,5,6,7-Hexahydroxyheptanoic acid

[0043] R₁=H, R₂=H, m=6, n=0

[0044] 14. Diphenyl 2-hydroxyacetic acid (benzilic acid)

[0045] R₁=C₆H₅, R₂=C₆H₅, m=1, n=0

[0046] 15. 4-Hydroxymandelic acid

[0047] R₁=C₆H₄(OH), R₂=H, m=1, n=0

[0048] 16. 4-Chloromandelic acid

[0049] R₁=C₆H₄ (Cl), R₂=H, m=1, n=0

[0050] 17. 3-Hydroxybutanoic acid

[0051] R₁=CH₃, R₂=H, m=1, n=1

[0052] 18. 4-Hydroxybutanoic acid

[0053] R₁=H, R₂=H, m=a, n=2

[0054] 19. 2-Hydroxyhexanoic acid

[0055] R₁=C₄H₉, R₂=H, m=1, n=0

[0056] 20. 5-Hydroxydodecanoic acid

[0057] R₁=C₇H₁₅, R₂=H, m=1, n=3

[0058] 21. 12-Hydroxydodecanoic acid

[0059] R₁=H, R₂=H, m=1, n=10

[0060] 22. 10-Hydroxydecanoic acid

[0061] R₁=H, R₂=H, m=1, n=8

[0062] 23. 16-Hydroxyhexadecanoic acid

[0063] R₁=H, R₂=H, m=1, n=14

[0064] 24. 2-Hydroxy-3-methylbutanoic acid

[0065] R₁=C₃H₇, R₂=H, m=1, n=0

[0066] 25. 2-Hydroxy-4-methylpentanoic acid

[0067] R₁=C₄H₉, R₂=H, m=1, n=0

[0068] 26. 3-Hydroxy-4-methoxymandelic acid

[0069] R₁=C₆H₃ (OH) (OCH₃), R₂=H, m=1, n=0

[0070] 27. 4-Hydroxy-3-methoxymandelic acid

[0071] R₁=C₆H₃ (OH) (OCH₃), R₂=H, m=1, n=0

[0072] 28. 2-Hydroxy-2-methylbutanoic acid

[0073] R₁=C₂H₅, R₂=CH₃, m=1, n=0

[0074] 29. 3-(2-Hydroxyphenyl) lactic acid

[0075] R₁=C₆H₄(OH) CH₂, R₂=H, m=1, n=0

[0076] 30. 3-(4-Hydroxyphenyl) lactic acid

[0077] R₁=C₆H₄ (OH) CH₂, R₂=H, m=1, n=0

[0078] 31. Hexahydromandelic acid

[0079] R₁=C₆H₁₁, R₂=H, m=1, n=0

[0080] 32. 3-Hydroxy-3-methylpentanoic acid

[0081] R₁=C₂H₅, R₂=CH₃, m=1, n=1

[0082] 33. 4-Hydroxydecanoic acid

[0083] R₁=C₆H₁₃, R₂=H, m=1, n=2

[0084] 34. 5-Hydroxydecanoic acid

[0085] R₁=C₅H₁₁, R₂=H, m=1, n=3

[0086] 35. Aleuritic acid

[0087] R₁=C₆H₁₂(OH), R₂=H, m=2, n=7

[0088] The linear lactic acid polymer is an intermolecular lactoneformed by elimination of one water molecule between the hydroxy group ofone molecule of lactic acid and the carboxylic group of a secondmolecule of lactic acid. The common linear lactic acid polymer maycontain 3 lactic acid units.

[0089] Ribonic acid is one of the stereoisomers of2,3,4,5-tetrahydroxypentanoic acid, and the corresponding lactone isribonolactone. Gluconic acid, galactonic acid, gulonic acid and mannonicacid are typical 2,3,4,5,6-pentahydroxyhexanoic acids and theircorresponding lactones are gluconolactone, galactonolactone,gulonolactone and mannonolactone respectively. The related compounds ofhydroxymonocarboxylic acids are ketomonocarboxylic acids which areformed from the former by a oxidation reaction or in vivo by adehydrogenase enzyme. For example, 2-ketopropanoic acid (pyruvic acid)and 2-hydroxypropanoic acid (lactic acid) are converted to each other invivo by the enzyme, lactate dehydrogenase. Although pure pyruvic acid(liquid form) can be kept in a refrigerator for an extended period oftime a composition containing pyruvic acid for topical use is not verystable at an elevated temperature. Therefore, for practical purposespyruvic acid esters are used instead.

[0090] The representative esters are methyl pyruvate, ethyl pyruvate,propyl pyruvate and isopropyl pyruvate. Other representativeketomonocarboxylic acids and their esters are phenyl pyruvic acid andits esters such as methyl phenyl pyruvate, ethyl phenyl pyruvate andpropyl phenyl pyruvate; formyl formic acid (2-ketoacetic acid) and itsesters such as methyl, ethyl and propyl formyl formate; benzoyl formicacid and its esters such as methyl, ethyl and propyl benzoyl formate;4-hydroxybenzoylformic acid and its esters; 4-hydroxyphenylpyruvic acidand its esters; 2-hydroxyphenylpyruvic acid and its esters.

[0091] Many hydroxy or ketomonocarboxylic acids are structurally relatedto amino acids either naturally occurring in proteins or not. Forexample alanine and pyruvic acid are interconverted to each other invivo by an enzyme alanine dehydrogenase or alanine ketoglutaratetransaminase. As mentioned earlier pyruvic acid and lactic acid areinterconverted to each other in vivo by the enzyme lactatedehydrogenase. Therefore, alanine, pyruvic acid and lactic acid arechemically related in that the amino group of alanine may be convertedto the keto group of pyruvic acid or the hydroxy group of lactic acid.The same relationships may apply to formyl formic acid and glycolic acidto glycine; hydroxpyruvic acid and glyceric acid to serine, phenylpyruvic acid and phenyl lactic acid to phenylalanine; 2-keto- and2-hydroxy-4 (methylthio) butanoic acids to methionine.

[0092] The second kind of hydroxyacid is hydroxydicarboxylic acid havingthe following chemical structure:

[0093] wherein

[0094] m=1, 2, 3, 4, 5, 6, 7, 8 or 9

[0095] n=0 or a numerical number up to 23

[0096] The hydroxydicarboxylic acid may also be present as a free acid,lactone or salt form. The lactone form could be either inter orintramolecular lactone. However, the common lactone is an intramolecularlactone with a ring structure formed by elimination of one or more watermolecule between a hydroxy group and one of the carboxylic groups. Sincethe hydroxydicarboxylic acid is organic in nature, it may form a salt ora complex with an inorganic or organic base such as ammonium hydroxide.sodium or potassium hydroxide, or triethanolamine.

[0097] The hydroxydicarboxylic acid and its related compounds may alsoexist as stereoisomers such as D, L, DL and meso forms.

[0098] The hydrogen atom attached to the carbon atom may be substitutedby a nonfunctional element such as F, Cl, Br, I, S or a radical such asa lower alkyl or alkoxy of saturated or unsaturated, having 1 to 9carbon atoms.

[0099] When n=0 and m=1 or more, the hydroxydicarboxylic acid is alsocalled aldaric acid. The name comes from the carbohydrate, and thecommon ones are saccharic acid and galactaric acid. Representativehydroxydicarboxylic acids are listed below:

[0100] 1. 2-Hydroxypropanedioic acid (Tartronic acid)

[0101] m=1, n=0

[0102] 2. 2-Hydroxybutanedioic acid (Malic acid)

[0103] m=1, n=1

[0104] 3. Erythraric acid and Threaric acid (Tartaric acid)

[0105] m=2, n=0

[0106] 4. Arabiraric acid, Ribaric acid, Xylaric acid and Lyxaric acid

[0107] m=3, n=0

[0108] 5. Glucaric acid (saccharic acid), Galactaric acid (Mucic acid),Mannaric acid, Gularic acid, Allaric acid, Altraric acid, Idaric acidand Talaric acid

[0109] m=4, n=0

[0110] Commercially available saccharolactone (D-saccharic acid 1,4-lactone) is an intramolecular lactone formed by elimination of onewater molecule between the hydroxy group at position 4 and thecarboxylic group at position 1.

[0111] The third type of hydroxyacid is a miscellaneous group ofcompounds which is not readily represented by the above genericstructure. of either the first type or the second type. Included in thethird type of hydroxyacids are the following:

[0112] Hydroxycarboxylic acid of

R(OH)_(m)(COOH)_(n)

[0113] Wherein m,n=1,2,3,4,5,6,7,8,or 9

[0114] R=H, alkyl, aralkyl or aryl group of saturated or unsaturated,straight or branched chain or cyclic form, having 1 to 25 carbon atoms.

[0115] citric acid, isocitric acid, citramalic acid, agaricic acid(n-hexadecylcitric acid), quinic acid, uronic acids including glucuronicacid, glucuronolactone, galacturonic acid, galacturonolactone,hydroxypyruvic acid, hydroxypyruvic acid phosphate, ascorbic acid,dihydroascorbic acid, dihydroxytartaric acid, 2-hydroxy-2-methylbutanoicacid, 1-hydroxy-1-cyclopropane carboxylic acid, 2-hydroxyhexanedial,5-hydroxylysine, 3-hydroxy-2-aminopentanoic acid, tropic acid,4-hydroxy-2, 2-diphenylbutanoic acid, 3-hydroxy-3-methylglutaric acid,and 4-hydroxy-3-pentenoic acid.

[0116] The third type of hydroxyacid may also be present as a free acid,lactone or salt form. The lactone form could be either an inter orintramolecular lactone, however, most common are intramolecular lactoneswith a ring structure. Commonly known glucuronolactone is a r-lactonei.e. 1,4-lactone of intramolecular type.

[0117] The hydroxyacid of the third type may also exist as stereoisomerssuch as D, L, DL and meso forms. The hydrogen atom attached to thecarbon atom may be substituted by a nonfunctional element such as F, Cl,Br, I, S or a radical such as a lower alkyl or alkoxy of saturated orunsaturated, having 1 to 9 carbon atoms.

[0118] Any hydroxyacid and related compound of the above three kinds maybe used as an additive in a combination composition to enhance thepercutaneous penetration or the therapeutic efficacy of cosmetic andpharmaceutical agents. The cosmetic and pharmaceutical agents mayinclude but not limited to: age spots and keratoses removing agents,vitamins, aloes, retinoids, sun screens; tanning, depigmenting andshampooing agents; antiperspirants, antiyeasts, antifungal,antibacterial and antiviral agents; topical bronchial dilators; topicalcardiovascular agents; keratoses, age spots and wrinkles removal agents,hair growth promoting agents and other dermatological agents.

[0119] Hydroxyacids and related compounds may also be used alone in theprophylactic and therapeutic treatment of cosmetic conditions ordermatologic disorders characterized by disturbed keratinization, aging,lipid metabolism or inflammation. The representative hydroxyacids arelisted below:

[0120] citramalic acid, tropic acid, benzilic acid, ribonic acid andribonolactone, gulonic acid and gulonolactone, 2,3,4-trihydroxybutanoicacid, 2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoicacid, 2-hydroxylauric acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid,aleuritic acid, 4-hydroxymandelic acid, 4-chloromandelic acid,2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid,3-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid,3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid,3-(2-hydroxyphenyl) lactic acid, 3-(4-hydroxyphenyl) lactic acid,hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid,1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxybutanoic acid,2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acid,10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxydecanoicacid, 5-hydroxydecanoic acid, and 4-hydroxy-2, 2-diphenylbutanoic acid.

Preparation of the Therapeutic Compositions

[0121] To prepare a therapeutic composition in solution form at leastone of the aforementioned enhancing compounds of hydroxyacids and acosmetic or pharmaceutical agent are dissolved in a solution which mayconsist of ethanol, water, propylene glycol, acetone or otherpharmaceutically acceptable vehicles. The concentration of hydroxyacidsmay range from 0.01 to 99 percent by weight of the total composition.The concentration of the cosmetic or pharmaceutical agent ranges from0.01 to 40 percent by weight of the total composition.

[0122] In the preparation of a therapeutic composition in cream orointment form at least one of hydroxyacids and one of cosmetic orpharmaceutic agents are initially dissolved in a solvent such as water,ethanol, acetone, propylene glycol or polysorbate 80. the solution thusprepared is then mixed in a conventional manner with commonly availablecream or ointment base such as hydrophilic ointment or petrolatum. Theconcentrations of hydroxyacids, cosmetic and pharmaceutical agents mayrange from 0.01 to 99 percent by weight of the total composition.

[0123] Therapeutic compositions of the instant invention may also beformulated in gel, lotion, shampoo, spray, stick or powder. A typicalgel composition of the instant invention utilizes at least one ofhydroxyacids and one of cosmetic or pharmaceutical agents dissolved in amixture of ethanol, water and propylene glycol in a volume ratio of40:40:20, respectively. A gelling agent such as hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose or ammoniatedglycyrrhizinate is then added to the mixture with agitation. Thepreferred concentration of the gelling agent may range from 0.1 to 4percent by weight of the total composition.

[0124] The following are illustrative examples of formulations andcompositions according to this invention. Although the examples utilizeonly selected compounds and formulations, it should be understood thatthe following examples are illustrative and not limitative. Therefore,any of the aforementioned hydroxyacids, cosmetic and pharmaceuticalagents may be substituted according to the teachings of this inventionin the following examples.

EXAMPLE 1

[0125] A prophylactic and therapeutic composition in solution form forage spots and for keratoses may be prepared as follows.

[0126] Malic acid 1 gram, gluconolactone 19 grams and citric acid 0.5gram are dissolved in a mixture of ethanol 30 ml, water 42 ml andglycerin 5 ml. Sodium bisulfite 0.5 g and hydroquinone 2 grams are addedwith stirring until a clear solution is obtained. The hydroxyacids,malic acid, gluconolactone and citric acid have been added a) asantioxidants to help stabilize the hydroquinone in the composition b) toenhance the penetration and the efficacy of hydroquinone c) to normalizethe disturbed keratinization in age spot and keratoses.

[0127] The composition thus formulated contains 2% hydroquinone, 1%malic acid, 19% gluconolactone, 0.5% citric acid, and has pH 3.3

EXAMPLE 2

[0128] A therapeutic composition in solution form for age spots and forkeratoses may be formulated as follows.

[0129] Alpha hydroxyisobutyric acid (Methyllactic acid) 20 grams andcitric acid 2 grams are dissolved in a mixture of ethanol 49 ml, water20 ml and propylene glycol 7 ml. Sodium bisulfite 0.5 g and hydroquinone2 grams are added with stirring until a clear solution is obtained. Thecomposition thus formulated contains 2% hydroquinone, 2% citric acid,20% methyllactic acid, and has pH 3.6.

EXAMPLE 3

[0130] A prophylactic and therapeutic composition containing minoxidiland lactic acid for hair growth and for prevention of hair loss on thescalp may be formulated as follows.

[0131] Minoxidil 2 grams and lactic acid 3 ml are dissolved in a mixtureof ethanol 80 ml and propylene glycol 15 ml with stirring until a clearsolution is obtained. The composition thus formulated contains 2%minoxidil, 3% lactic acid, and has pH 4.7. The lactic acid has beenadded to help minoxidil dissolved into solution, to enhance thepenetration and the efficacy of minoxidil for hair growth.

EXAMPLE 4

[0132] A prophylactic and therapeutic composition in solution form forhair growth on the scalp may be formulated as follows.

[0133] Minoxidil 2 grams and ethyl pyruvate 2 ml are dissolved in amixture of ethanol 80 ml and propylene glycol 16 ml. The compositionthus formulated contains 2% minoxidil, 2% ethyl pyruvate, and has pH5.0. The ketoacid ester, ethyl pyruvate has been added to enhance thepenetration and the efficacy of minoxidil for hair growth on the scalp.

EXAMPLE 5

[0134] A therapeutic composition containing anthralin and hydroxyacidfor psoriasis may be formulated as follows.

[0135] Anthralin powder 0.5 gram and alpha hydroxyisobutyric acid 4grams are dissolved in a mixture of ethanol 50 ml, acetone 30 ml anddiisopropyl adipate 16 ml with stirring until a clear yellowish solutionis obtained. The composition thus formulated contains 0.5% anthralin, 4%alpha hydroxyisobutyric acid, and has pH 4.2. The hydroxyacid has beenadded to enhance the penetration and the efficacy of anthralin forpsoriasis.

EXAMPLE 6

[0136] A therapeutic composition containing thionicotinamide andhydroxyacid for psoriasis, keratoses and warts may be formulated asfollows.

[0137] Thionicotinamide 2 grams and lactic acid 20 ml are dissolved in amixture of ethanol 40 ml, water 30 ml and propylene glycol 8 ml withstirring until a clear yellowish solution is obtained. The compositionthus formulated contains 2% thionicotinamide, 20% lactic acid, and haspH 3.3. The lactic acid has been added to enhance the penetration andthe efficacy of thionicotinamide, and also to normalize the disturbedkeratinization in psoriasis, keratoses and warts.

EXAMPLE 7

[0138] A therapeutic composition containing 6-aminonicotinamide andhydroxyacid for psoriasis, keratoses and warts may be formulated asfollows.

[0139] 6-Aminonicotinamide 1 gram and glycolic acid 19 grams aredissolved in a mixture of ethanol 40 ml, water 32 ml and propyleneglycol 8 ml with stirring until a clear solution is obtained. Thecomposition thus formulated contains 1% 6-aminonicotinamide, 19%glycolic acid, and has pH 3.0. The glycolic acid has been added toenhance the penetration and the efficacy of 6-Aminonicotinamide, andalso to normalize the disturbed keratinization in psoriasis, keratosesand warts.

EXAMPLE 8

[0140] A therapeutic composition containing clotrimazole and hydroxyacidfor fungal infection may be formulated as follows.

[0141] Clotrimazole 1 gram and lactic acid 4 ml are dissolved in 4 ml ofethanol, and the solution thus obtained is mixed with 91 grams ofhydrophilic ointment USP. The mixing is continued until a uniformconsistency is obtained. The composition thus formulated contains 1%clotrimazole, 4% lactic acid, and has pH 3.2. The lactic acid has beenadded to enhance the penetration and the efficacy of clotrimazole forathletes foot, and also to speed up healing and normalize the disturbedkeratinization.

EXAMPLE 9

[0142] A prophylactic and therapeutic composition containingchlorhexidine and hydroxyacid as general antiseptics on skin, and forprophylactic and therapeutic treatment of acne may be formulated asfollows. Chlorhexidine diacetate 1 gram and benzilic acid 5 grams aredissolved in a mixture of ethanol 70 ml, water 10 ml and propyleneglycol 14 ml with stirring until a clear solution is obtained. Thecomposition thus formulated contains 1% chlorhexidine, 5% benzilic acid,and has pH 4.4. Benzilic acid has been added to enhance theantibacterial effect of chlorhexidine, to eliminate the oiliness of theskin, and to improve the acne lesions.

EXAMPLE 10

[0143] A prophylactic and therapeutic composition containing benzilicacid as the only active ingredient for oily skin, acne, skin cleansingand skin malodor may be formulated as follows.

[0144] Benzilic acid 7 grams is dissolved in a mixture of ethanol 60 ml,water 20 ml and propylene glycol 13 ml with stirring until a clearsolution is obtained. The composition thus prepared contains 7% benzilicacid, and has pH 3.0.

EXAMPLE 11

[0145] A therapeutic composition containing tropic acid as the onlyactive ingredient for severe dry skin may be formulated as follows.

[0146] Tropic acid 10 grams is dissolved in 20 ml of ethanol, and thesolution thus obtained is mixed with 70 grams of hydrophilic ointmentUSP. The mixing is continued until a uniform consistency is obtained.The composition thus formulated contains 10% tropic acid as an activeingredient, and has pH 3.7.

EXAMPLE 12

[0147] A prophylactic and therapeutic composition containingribonolactone as the only active ingredient for oily skin, acne and skincleansing may be formulated as follows.

[0148] Ribonolactone 4 grams is dissolved in a mixture of ethanol 36 mland water 60 ml with stirring until a clear solution is obtained. Thecomposition thus prepared contains 4% ribonolactone as an activeingredient, and has pH 3.8.

EXAMPLE 13

[0149] A therapeutic composition containing hydrocortisone and tropicacid for inflammatory and/or pruritic skin disorders may be formulatedas follows.

[0150] Hydrocortisone 0.5 gram and tropic acid 5 grams are dissolved in10 ml of ethanol and 4 ml of acetone, and the solution thus obtained ismixed with 80 grams of hydrophilic ointment USP. The mixing is continueduntil a uniform consistency is obtained. The composition thus formulatedcontains 0.5% hydrocortisone and 5% tropic acid as active ingredients,and has pH 3.4. The tropic acid has been added to enhance thepenetration and the efficacy of hydrocortisone and also to normalize thedisturbed keratinization.

EXAMPLE 14

[0151] A therapeutic composition containing triamcinolone acetonide andbenzilic acid for eczema, psoriasis and other inflammatory and pruriticskin disorders may be formulated as follows.

[0152] Triamcinolone acetonide 0.1 gram and benzilic acid 5 grams aredissolved in 10 ml of ethanol, and the solution thus obtained is mixedwith 85 grams of hydrophilic ointment USP. The mixing is continued untila uniform consistency is obtained. The composition thus formulatedcontains 0.1% triamcinolone acetonide, 5% benzilic acid, and has pH 3.4.The benzilic acid has been added to enhance the penetration and theefficacy of triamcinolone acetonide, and also to normalize the disturbedkeratinization in eczema, psoriasis and other inflammatory skindisorders.

EXAMPLE 15

[0153] A prophylactic and therapeutic composition containingdipyridamole and lactic acid for hair growth and for prevention of hairloss on the scalp may be formulated as follows.

[0154] Dipyridamole 2 grams and lactic acid 4 ml are dissolved in amixture of ethanol 80 ml and propylene glycol 14 ml with stirring untila clear yellowish solution is obtained. The composition thus formulatedcontains 2% dipyridamole, 4% lactic acid, and has pH 4.4. The lacticacid has been added to help dipyridamole dissolved into solution, toenhance the penetration and the efficacy of dipyridamole for hair growthand for preventing hair loss.

EXAMPLE 16

[0155] A therapeutic composition containing clobetasol propionate andagaricic acid for eczema, psoriasis and other inflammatory and pruriticskin disorders may be formulated as follows.

[0156] Agaricic acid fine powder 2 grams and 98 grams of clobetasolpropionate cream are mixed until a uniform consistency is obtained. thecomposition thus formulated contains approximately 0.05% clobetasolpropionate, 2% agaricic acid, and has pH 4.3. The agaricic acid has beenadded to enhance the penetration and the efficacy of clobetasolpropionate, and also to normalize the disturbed keratinization ineczema, psoriasis and other inflammatory skin disorders.

EXAMPLE 17

[0157] A therapeutic composition containing betamethasone dipropionateand benzilic acid for eczema, psoriasis, contact dermatitis and otherinflammatory and pruritic skin disorders may be formulated as follows.

[0158] Benzilic acid powder 5 grams and 95 grams of betamethasonedipropionate ointment are mixed until a uniform consistency is obtained.the composition thus formulated contains approximately 0.05%betamethasone dipropionate and 5% benzilic acid. The benzilic acid hasbeen added to enhance the penetration and the efficacy of betamethasonedipropionate, and also to normalize the disturbed keratinization ineczema, psoriasis and other inflammatory skin disorders.

EXAMPLE 18

[0159] A prophylactic and therapeutic composition containing aloe, malicacid and gluconolactone for oily skin and acne may be formulated asfollows.

[0160] Aloe powder 200 fold 0.2 gram and ammoniated glycyrrhizinate 2grams are mixed with water 61 ml and propylene glycol 2 ml. The mixtureis heated to 50° C. until the aloe powder and the ammoniatedglycyrrhizinate are completely dissolved. Ethanol 10 ml is added to thesolution followed by the addition of partially neutralized malic acidstock solution 3 ml and gluconolactone stock solution 22 ml withstirring. The warm solution is poured into container jars beforecooling. The gel composition thus formulated contains 40% aloe, 1% malicacid, 9% gluconolactone, and has pH 4.0. Malic acid and gluconolactonehave been added to enhance the skin softness and smoothness by aloe, andalso to normalize any disturbed keratinization of the skin.

EXAMPLE 19

[0161] A sun screen composition containing octyl dimethyl PABA,dioxybenzone and lactic acid may be formulated as follows. Octyldimethyl PABA $ grams, dioxybenzone 3 grams and lactic acid 2 ml. aredissolved in a mixture of ethanol 65 ml, water 10 ml and propyleneglycol 15 ml with stirring until a clear solution is obtained. Thecomposition thus formulated contains 5% octyl dimethyl PABA, 3%dioxybenzone, 2% lactic acid, and has pH 3.6. The lactic acid has beenadded to substantiate the absorption of sunscreen agents, octyl dimethylPABA and dioxybenzone, and to enhance the sun screen effect.

EXAMPLE 20

[0162] A prophylactic and therapeutic composition containingtetracycline and glycolic acid for oily skin and acne may be formulatedas follows.

[0163] Tetracycline 3 grams and glycolic acid 5 grams are dissolved in amixture of ethanol 40 ml, water 40 ml and propylene glycol 12 ml withstirring until the tetracycline and glycolic acid are completelydissolved. The composition thus formulated contains 3% tetracycline, 5%glycolic acid, and has pH 3.4. The glycolic acid has been added to helptetracycline dissolved into the solution, to enhance the penetration andthe efficacy of tetracycline, and to normalize the disturbedkeratinization in acne.

EXAMPLE 21

[0164] A therapeutic composition containing griseofulvin and methylpyruvate for fungal infection of nails may be formulated at follows.

[0165] Griseofulvin 1 gram and methyl pyruvate 2 ml are dissolved in amixture of 2-pyrrolidone 20 ml. PEG-400 47 ml and ethanol 30 ml withstirring until the griseofulvin is completely dissolved. The compositionthus formulated contains 1% griseofulvin, 2% methyl pyruvate, and has pH4.4. The methyl pyruvate has been added to help griseofulvin dissolveinto the solution, to enhance the penetration and the efficacy ofgriseofulvin, and to normalize the disturbed keratinization in nails.

EXAMPLE 22

[0166] A therapeutic composition containing lidocaine and atrolacticacid for pruritic skin may be formulated as follows.

[0167] Lidocaine 2 grams and atrolactic acid hemihydrate 3 grams aredissolved in a mixture of ethanol 40 ml, water 40 ml and propyleneglycol 15 ml with stirring until the lidocaine and atrolactic acid arecompletely dissolved. The composition thus formulated contains 2%lidocaine, 3% atrolactic acid, and has pH 4.6. The atrolactic acid hasbeen added to help lidocaine dissolved and stabilized in the solutionand to enhance the efficacy of lidocaine for pruritic skin.

EXAMPLE 23

[0168] A prophylactic and therapeutic composition containing retinoicacid and ethyl pyruvate for oily skin and acne may be formulated asfollows.

[0169] Retinoic acid, all-trans 0.1 gram and ethyl pyruvate 2 ml aredissolved in a mixture of ethanol 80 ml, water 10 ml and propyleneglycol 8 ml with stirring until a yellowish solution is obtained. Thecomposition thus formulated contains 0.1% vitamin A acid, 2% ethylpyruvate, and has pH 3.6. The ethyl pyruvate has been added to enhancethe penetration and the efficacy of retinoic acid, and to normalize thedisturbed keratinization in acne.

EXAMPLE 24

[0170] A prophylactic and therapeutic composition containingerythromycin and aleuritic acid for oily skin and acne may be formulatedas follows.

[0171] Erythromycin 2 grams and aleuritic acid 2 grams are dissolved ina mixture of ethanol 50 ml, water 40 ml and propylene glycol 6 ml withstirring until a clear solution is obtained. The composition thusformulated contains 2% erythromycin, 2% aleuritic acid, and has pH 5.7.The aleuritic acid has been added to help erythromycin dissolve into thesolution, to enhance the penetration and the efficacy of erythromycin,and to normalize the disturbed keratinization in acne.

EXAMPLE 25

[0172] A therapeutic composition containing P-hydroxymandelic acid fordry skin may be formulated as follows.

[0173] P-Hydroxymandelic acid 10 grams is dissolved in 20 ml of ethanol,and the pinkish solution thus obtained is mixed with 70 grams ofhydrophilic ointment USP with stirring until a uniform consistency isobtained. The composition thus formulated contains 10% P-hydroxymandelicacid as an active ingredient, and has pH 3.2. P-Hydroxymandelic acid hasbeen incorporated into the composition to alleviate any scaly or flakyskin, and to change the dry skin into normal smooth and soft skin.

EXAMPLE 26

[0174] A therapeutic composition containing hydroquinone and lactic acidin solution form for age spots, keratoses, melasmas, lentigines andother pigmented skin spots may be formulated as follows.

[0175] Lactic acid 10 ml, hydroquinone 4 grams and sodium metabisulfite0.6 gram are dissolved in a mixture of ethanol 70 ml, water 10 ml andpropylene glycol 6 ml with stirring until a clear solution is obtained.The composition thus formulated contains 4% hydroquinone, 10% lacticacid, and has pH 4.0. The lactic acid has been added to help stabilizeand enhance the penetration and the efficacy of hydroquinone, and alsoto normalize the disturbed keratinization in the skin lesions. Thecomposition thus formulated is packaged in felt pens for controlleddelivery to skin lesions.

EXAMPLE 27

[0176] A therapeutic composition containing hydroquinone and glycolicacid in solution form for age spots, keratoses, melasmas, lentigines andother pigmented skin spots may be formulated as follows.

[0177] Glycolic acid 8 grams, hydroquinone 5 grams and sodiummetabisulfite 0.5 gram are dissolved in a mixture of ethanol 70 ml,water 10 ml and propylene glycol 7 ml with stirring until a clearsolution is obtained. The composition thus formulated contains 5%hydroquinone, 8% glycolic acid, and has pH 3.9. The glycolic acid hasbeen added to help stabilize and enhance the penetration and theefficacy of hydroquinone, and also to normalize the disturbedkeratinization in the skin lesions. The composition thus prepared ispackaged in felt pens for controlled delivery to skin lesions.

EXAMPLE 28

[0178] A therapeutic composition containing hydroquinone and 2-methyl2-hydroxypropanoic acid in solution form for age spots, keratoses,melasmas, lentigines and other pigmented skin spots may be formulated asfollows.

[0179] 2-Methyl 2-hydroxypropanoic acid 12 grams, hydroquinone 4 gramsand sodium bisulfite 0.3 gram are dissolved in a mixture of ethanol 60ml, water 20 ml and propylene glycol 4 ml with stirring until a clearsolution is obtained. The composition thus formulated contains 4%hydroquinone, 12% 2-methyl 2-hydroxypropanoic acid, and has pH 4.0. Thecomposition solution is packaged in felt pens for controlled delivery toskin lesions. The 2-methyl 2-hydroxypropanoic acid has been added tohelp stabilize and enhance the penetration and the efficacy ofhydroquinone, and also to normalize the disturbed keratinization in theskin lesions.

EXAMPLE 29

[0180] A composition containing hydroquinone alone in solution form forage spots and keratoses studies may be formulated as follows.

[0181] Hydroquinone 5 grams and sodium metal bisulfite 0.5 gram aredissolved in a mixture of ethanol 70 ml, water 15 ml and propyleneglycol 10 ml with stirring until a clear solution is obtained. Thecomposition thus prepared contains 5% hydroquinone and has pH 6.0. Thecomposition solution is packaged in felt pens for comparative studies;with or without hydroxyacids on age spots and keratoses.

Test Results

[0182] In order to determine whether addition of a hydroxyacid in thecomposition could enhance the therapeutic action of a cosmetic orpharmaceutical agent a total of more than 55 volunteers and patientshaving different skin disorders participated in these studies. Eachparticipating subject was given two preparations; i.e. with or withoutthe addition of a hydroxyacid in the therapeutic composition.

[0183] Topical applications were carried out either by bilateral orsequential comparison, In bilateral comparison the subject wasinstructed to apply one preparation on one side of the body and theother one on the other side of the body. For psoriasis, eczema, severedry skin, athlete's foot, etc., where both sides were involved, thesubject was instructed to apply two to three times daily one medicationon one side of the body for a period of up to several months of time. Inthe pulse treatment for psoriasis or other inflammatory diseases themedication was applied only once every three days or twice a week. Themedication was discontinued whenever a total remission of the ginlesions occurred prior to the test period of up to several months.

[0184] For the scalp or face involvement such as in dandruff, oily skin,acne and seborrheic dermatitis the subject was instructed to apply twoto three time daily one medication on one side of the scalp or the faceand the other medication on the other side of the scalp or the face fora period of up to 12 weeks of time. For age spots, keratoses or wartsthe medication was continued for up to 4 months of time.

[0185] Sequential administrations of medications were carried outwhenever the bilateral comparison was difficult. for example in pruriticconditions the subject was instructed to apply four time daily or asoften as necessary one medication on the pruritic, lesions for two days,then switched to the other medication on the same lesions for anothertwo days, thus to compare which medication was more effective inrelieving the itching.

[0186] 1. Dry skin.

[0187] Human subjects having ordinary dry skin or with moderate degreesof dry skin as evidenced by dry, flaking and cracking of the skin wereinstructed to apply topically the lotion, cream or ointment containing 3to 7 percent of hydroxyacids of the instant invention on the affectedskin areas. Topical application, two to three times daily, was continuedfor two to three weeks. In all the nine subjects tested, the feeling ofthe skin dryness disappeared within a week of topical application. Therough and cracked skin became less pronounced and the skin appearednormal and felt smooth after 10 days of topical treatment.

[0188] The ordinary dry skin conditions once restored to normalappearing skin remained improved for some time until causes of dry skin,such as low humidity, cold weather, excessive contact pressure,detergents, soaps,'solvents, chemicals, etc., again caused recurrence ofthe dry skin condition. On continued use it was also found that twicedaily topical application of a composition containing one or morehydroxyacids of instant invention prevented the development of new dryskin lesions.

[0189] In severe dry skin the skin lesions are different from the above.The involved skin is hyperplastic, fissured and has thick adherentscales. The degree of thickening is such that lesions are palpably andvisually elevated. The thickened adherent scales cause the surface ofinvolved skin to be markedly rough and uneven. The two attributes ofthickness and texture can be quantified to allow objective measurementof degree of improvement from topically applied therapeutic testmaterials as follows: DEGREE OF IMPROVEMENT None Mild ModerateSubstantial Complete (0) (1+) (2+) (3+) (4+) THICKNESS Highly DetectableReadily Barely Normal elevated reduction apparent elevated thicknessreduction TEXTURE Visibly Palpably Uneven but Slightly Visibly and roughrough not rough uneven palpably smooth

[0190] By means of such parameters degrees of change in lesions can benumerically noted and comparisons made of one treated site to another.

[0191] In order to evaluate the hydroxyacids and their related compoundsof the instant invention a total of six patients with severe dry skinconditions or ichthyosis were treated with the compositions containing 7to 15% of hydroxyacids as described in the Examples.

[0192] Treated areas were of a size convenient for topical applications,i.e., circles 5 cm in diameter demarcated with a plastic ring of thatsize inked on a stamp pad. The medicinal creams or ointments weretopically applied by the patient in an amount sufficient to cover thetreatment sites. Applications were made three time daily and withoutocclusive dressings. Applications were discontinued at any time whenresolution of the lesion on the treatment area was clinically judged tobe complete.

[0193] The test results on patients with severe dry skin are summarizedon the following table. Topical Effectiveness of Hydroxyacids on SevereDry Skin Number of Therapeutic Compounds Patients Effectiveness 1.Tropic acid 4 4+ 2. Benzilic acid 5 4+ 3. Ribonolactone 3 3+ 4.4-Hydroxymandelic acid 2 3+ 5. 3-Chloro 4-hydroxymandelic acid 2 3+ 6.3,4-Dihydroxymandelic acid 2 3+

[0194] 2. Psoriasis

[0195] The involved skin in psoriasis is hyperplastic (thickened),erythematous (red or inflamed), and has thick adherent scales. thedegree of thickening is such that lesions are elevated up to 1 mm abovethe surface of adjacent normal skin; erythema is usually an intense red;the thickened adherent scales cause the surface of involved skin to bemarkedly rough and uneven. These three attributes of thickness, colorand texture can be quantified to allow objective measurement of degreeof improvement from topically applied therapeutic test materials asfollows. DEGREE OF IMPROVEMENT None Mild Moderate Substantial Complete(0) (1+) (2+) (3+) (4+) Thickness Highly Detectable Readily BarelyNormal elevated reduction apparent elevated thickness Texture VisiblyPalpably Uneven but Slightly Visibly and rough rough not rough unevenpalpably smooth Color Intense Red Dark Pink Light Normal skin red pinkcolor

[0196] By means of such parameters degree of improvements in psoriaticlesions can be numerically recorded and comparisons made of one treatedsite to another. The treatment schedule was quite different from thepreviously described in that the present study was employing a “PulseTreatment.” Instead of several times daily application the therapeuticcomposition of antipsoriatic agent with or without a hydroxyacid insolution form was topically applied to the involved skin only once inevery three days or twice a week. The test results on patients havingpsoriasis are summarized on the following table. Topical Effects onPsoriasis of Antipsoriatic Agents With or without Hydroxyacids Thera-Number peutic of Effective- Compositions Patients ness Thionicotinamide3% alone 6 2+ with 10% Lactic acid 6 4+ with 5% Glycolic acid 4 4+ with5% 2-methyl 2-hydroxypropanoic acid 3 4+ 6-Aminonicotinamide 1% alone 53+ with 10% Lactic acid 5 4+ with 10% Glycolic acid 4 4+ Betamethasonedipropionate 0.05% ointment alone 5 3+ with 5% Benzilic acid 4 −4+  with5% Tropic acid 3 4+ with 5% 2-Methyl 2-Hydroxypropanoic acid 3 4+Clobetasol propionate 0.05% cream alone 4 2+ with 5% Benzilic acid 3 3+with 5% Tropic acid 2 3+ with 5% 2-Methyl 2-hydroxypropanoic acid 3 3+

[0197] In a topical treatment of eczema patients, betamethasonedipropionate or clobetasol propionate alone at 0.05% would achieve onlya 3+ improvement on all the eczema patients tested. As shown by thetable with the additional of 5% gluconolactone or ribonolactonebetamethasone dipropionate or clobetasol propionate could attain a 4+maximal clearing on all the eczema patients tested. Topical Effects onEczema of Corticosteroids With and Without Hydroxyacid Lactone Number ofTherapeutic Composition Patients Effectiveness Betamethasonedipropionate 0.05% alone 3 3+ with 5% Gluconolactone 3 4+ with 5%Ribonolactone 2 4+ Clobetasol propionate 0.05% alone 4 3+ with 5%Gluconolactone 4 4+ with 5% Ribonolactone 3 4+

[0198] 3. Age Spots, Wrinkles, Keratoses and Pigmented Skin lesions.

[0199] Therapeutic compositions packaged in felt pens as described inExamples were provided to 14 patients for treatment of age spots,wrinkles, keratoses and other pigmented skin spots. Each participatingpatient received two felt pens; i.e. with or without the addition ofhydroxyacid to the composition containing hydroquinone. The patientswere instructed to apply topically one medication on one side of thebody such as on the back of the left hand and the other medication onthe other side of the body such as on the back of the right hand.Specific instructions were given to the patients that the medicationswere applied twice daily and discretely only to the skin lesions of agespots, wrinkles, keratoses, melasmas, lentigines or other pigmented skinspots.

[0200] Within one to three weeks, improvement of age spots and keratoseswas clinically discernible. After one to three months substantialeradication of age spots, wrinkles and keratoses occurred in all thepatients tested. Complete eradication of age spots usually occurredwithin two to four months of topical administration in most cases.Therapeutic compositions containing higher concentrations ofhydroxyacids (10 to 20%) and hydroquinone (3 to 5%) were judged to bemore efficient in eradicating age spots, wrinkles and keratoses withinshorter periods of time. Without the addition of a hydroxyacid to thecomposition of hydroquinone, eradication of age spots, wrinkles orkeratoses did not occur within four months of time.

[0201] It was also found that while compositions containing hydroxyacidswithout hydroquinone were effective for eradication of keratoses andwrinkles, the compositions were not efficient in eradicating pigmentedage spots, melasmas or lentigines within 4 months of time. In any case,with the addition of a hydroxyacid to the composition containinghydroquinone, pigmented age spots, melasmas, lentigines and otherpigmented skin spots had been substantially eradicated.

[0202] 4. Acne.

[0203] Therapeutic compositions containing tetracycline, erythromycin orchlorhexidine with or without the addition of a hydroxyacid wereprovided to 9 patients having papulopustular or pustular lesions ofacne. Each participating patient received two medications, with orwithout the addition of a hydroxyacid to the composition containing anantibiotic. The patients were instructed to apply topically onemedication on one side of the body such as the left side forehead, face,back or chest, and the other medication on the other side of the bodysuch as right side forehead, face, back or chest. Twice dailyadministration was continued for 4 to 12 weeks.

[0204] The degree and rate of improvement on acne lesions wereclinically evaluated, and comparison was made between the two sides; oneside with and the other side without a hydroxyacid in the compositionscontaining an antibiotic. It was found that the degree and rate ofimprovement on acne lesions were substantially better on the sidetreated with a combination composition containing both the hydroxyacidand the antibiotic as compared to that of the antibiotic alone. The timefor complete clearing of acne lesions treated with a combinationcomposition varied from 4 to 12 weeks of time, with an average time of 8weeks, whereas complete clearing with that of the antibiotic aloneranged from 8 weeks to 9 months, with an average of 4 months.

[0205] 5. Preventing Hair Loss and for Hair Growth.

[0206] Prophylactic and therapeutic compositions containing minoxidil ordipyridamole with or without a hydroxyacid or related compound wereprovided to 6 human subjects having a progressive loss of hair on thescalp. Each participating subject received two medications; i.e. with orwithout the addition of a hydroxyacid to the composition containingminoxidil or dipyridamole. The subjects were instructed to applytopically one medication on one side of the scalp and the othermedication on the other side of the scalp. Twice daily topicalapplications were continued for 2 to 6 months. Clinical evaluation showsthat the combination compositions containing minoxidil or dipyridamoleand a hydroxyacid or related compound were therapeutically moreefficient in preventing the hair loss and enhancing hair growth on thescalp.

[0207] Therapeutic compositions containing clotrimazole or griseofulvinwith or without the addition of a hydroxyacid were provided to 6patients having recurrent fungal infections of the foot; i.e. athlete'sfoot with or without toe nail involvement. Each participating patientreceived two medications with or without the addition of a hydroxyacidto the composition containing clotrimazole or griseofulvin. The patientswere instructed to apply topically one medication on one side of thebody such as left foot, and the other medication on the other side ofthe body such as right foot. Three time daily applications werecontinued for one to two weeks. When nail infections were involved thetopical application was continued for up to 4 months using thecompositions containing griseofulvin with or without the addition of ahydroxyacid.

[0208] The degree and rate of improvement on skin lesions wereclinically evaluated, and comparison was made one side of the bodyagainst the other. It was found that the skin lesions improved muchfaster with the compositions containing both the antifungal agent andthe hydroxyacid. The presence of hydroxyacid appeared to enhance theefficacy of the antifungal agent, and also to eliminate the discomfortssuch as itching, tingling, burning and heat due to the fungal infection.Generally the infected skin healed within a week from topicalapplication of the compositions containing an antifungal agent and ahydroxyacid. When toe nails were involved in the fungal infection thecomplete healing and regrowth of nails usually took several months oncontinued topical application of medications containing griseofulvin anda hydroxyacid.

[0209] The hydroxyacids and related compounds which may be useful asdermatologic agents for various conditions and disorders including agespots, keratoses, skin wrinkles etc. or as additives to enhancetherapeutic effects of other cosmetic or pharmaceutical agents include2-Hydroxyacetic acid; 2-hydroxypropanoic acid; 2-methyl2-hydroxypropanoic acid: 2-hydroxybutanoic acid; phenyl 2-hydroxyaceticacid; phenyl 2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyaceticacid; 2,3-dihyroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;2,3,4,5,6-pentahydroxyhexanoic acid; 2-hydroxydodecanoic acid;2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoicacid; diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid;4-chloromandelic acid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid;2-hydroxyhexanoic acid; 5-hydroxydodecanoic acid; 12-hydroxydodecanoicacid; 10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid;2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid;3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxphenyl) lactic acid;3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid. 2-Hydroxypropanedioic acid;2-hydroxybutanedioic acid; erythraric acid; threaric acid; arabiraricacid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid;galactaric acid; mannaric acid; gularic acid; allaric acid; altraricacid; idaric acid; talaric acid; 2-hydroxy-2-methylbutanedioic acid.

[0210] Citric acid, isocitric acid, agaricic acid, quinic acid,glucuronic acid, glucuronolactone, galacturonic acid,galacturonolactone, uronic acids, uronolactones, ascorbic acid,dihydroascorbic acid, dihydroxytartaric acid, tropic acid,ribonolactone, gluconolactone, galactonolactone, gulonolactone,mannonolactone, citramalic acid.

[0211] Pyruvic acid, hydroxypyruvic acid, hydroxypyruvic acid phosphate,their esters; methyl pyruvate, ethyl pyruvate, propyl pyruvate,isopropyl pyruvate; phenyl pyruvic acid, its esters; methyl phenylpyruvate, ethyl phenyl pyruvate, propyl phenyl pyruvate; formyl formicacid; its esters; methyl formyl formate, ethyl formyl formate, propylformyl formate; benzoyl formic acid, its esters; methyl benzoyl formate,ethyl benzoyl formate and 3 propyl benzoyl formate; 4-hydroxybenzoylformic acid, its esters; 4-hydroxyphenyl pyruvic acid, its esters;2-hydroxyphenyl pyruvic acid and its esters.

[0212] The invention may be embodied in other specific forms withoutdeparting from the spirit or essential characteristics thereof. Thepresent embodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims and all changes which come within themeaning and equivalency of the claims are therefore intended to beembraced therein.

What is claimed is:
 1. A method for enhancing the therapeutic effect ofa composition comprising a cosmetic or pharmaceutical agent in apharmaceutically acceptable vehicle for topical application to the skinof humans or animals comprising: admixing with said composition anenhancing effective amount of at least one member selected from thegroup consisting of hydroxycarboxylic acid and related ketocarboxylicacid and ester, lactone or salt forms thereof.
 2. The method of claim 1wherein said cosmetic or pharmaceutical agent is a member selected fromthe group consisting of age spots, wrinkles and keratoses removingagents; analgesics, anesthetics, antiacne agents, antibacterials,antiyeasts, antifungals, antivirals; antiburn, antidandruff,antidermatitis, antipruritic, antiperspirant, antiinflammatory,antiaging, antihyperkeratolytic, antidryskin, antipsoriasis,antiseborrhea, astringent agents; skin softeners and emollients; coaltar, bath oils, sulfur, rinse conditioners; hair growth and hairremoving agents; keratolytics, moisturizers, powders, shampoos, skinbleaches, skin protectants, soaps, cleansers, sunscreens, wart removers,vitamins, tanning agents; topical antihistamins, hormones, retinoids,vasodilators, bronchial dilators, topical cardiovasculars anddermatologicals.
 3. The method of claim 1 wherein said cosmetic orpharmaceutical agent is a member selected from the group consisted of:aloe; 9-aminoacridine; PABA and its esters, acyclovir, amphotericins;benzoyl peroxide; clindamycin, chloramphenicol; clotrimazole,candicidin; cromolyn, clindamycin, crotamiton, coal tar; doxycycline;dipyridamole, dioxybenzone, diazoxide, diphenylhydantoin; ephedrine,erythromycin; fluorouracil, flucytosine; gentamicin, griseofulvin,gramicidin; halothane, hydroquinone and its monomethyl and benzylethers; haloprogin, hydralazine; idoxuridine, kanamycin, ketoconazole,lidocaine, miconazole, metronidazole, minoxidil, minocycline,meclocycline, metronidazole, nitroglycerine, nystatin, neomycin,oxybenzone, oxytetracycline, procaine, polymyxins, povidone-iodine,phenytoin, prazosin, retinoic acid and other retinoids, spironolactone,sulfonamides, sulfacytosine, spectinomycin, sulfamethoxazole,sulfisoxazoles, sulfamethizole, salicylic acid, selenium sulfide,sulfer, theophylline, tobramycin, tetracycline, tolnaftate,trimethoprin, troleandomycin, vitamins, vancomycin and zinc pyrithione.4. The method of claim 1 wherein said hydroxycarboxylic acid ishydroxymonocarboxylic acid having the following chemical structuralformula: R₁(CR₂OH)_(m)(CH₂)_(n)COOH wherein R₁, R₂=H, alkyl, aralkyl oraryl group of saturated or unsaturated, straight or branched chain orcyclic form, having 1 to 25 carbon atoms. m=1,2,3,4,5,6,7,8 or 9 n=0 ora numerical number up to 23 present as free acid, lactone or salt form,and as optically active or inactive isomer such as D, L, and DL forms;the hydrogen atom attached to the carbon atom may be substituted by anonfunctional F, Cl, Br, I, or S atom or a lower alkyl or alkoxysaturated or unsaturated radical, having 1 to 9 carbon atoms.
 5. Themethod of claim 4 wherein said hydroxymonocarboxylic acid is a memberselected from the group consisted of 2-hydroxyacetic acid;2-hydroxypropanoic acid; 2-methyl 2-hydroxypropanoic acid;2-hydroxybutanoic acid; phenyl 2-hydroxyacetic acid; phenyl 2-methyl2-hydroxyacetic acid; 3-phenyl 2-hydroxypropanoic acid;2,3-dihydroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6-pentahydroxyhexanoic acid;2-hydroxydodecanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoic acid;diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid; 4-chloromandelicacid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid; 2-hydroxyhexanoicacid; 5-hydroxydodecanoic acid; 12-hydroxydodecanoic acid;10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid;2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid;3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxyphenyl) lactic acid;3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid.
 6. The method of claim 4 whereinsaid hydroxymonocarboxylic acid is a member derived from an amino acidby substituting the amino group with a hydroxy group.
 7. The method ofclaim 4 wherein said lactone is an intermolecular or intramolecularlactone including linear acid polymer, ribonolactone, gluconolactone,galactonolactone, gulonolactone and mannonolactone.
 8. The method ofclaim 1 wherein said compound is a keto or hydroxyketomonocarboxylicacid selected from the group consisting of pyruvic acid, hydroxypyruvicacid, hydroxypyruvic acid phosphate, methyl pyruvate, ethyl pyruvate,propyl pyruvate, isopropyl pyruvate, phenyl pyruvic acid, methyl phenylpyruvate, ethyl phenyl pyruvate, propyl phenyl pyruvate; formyl formicacid, methyl formyl formate, ethyl formyl formate, propyl formylformate, benzoyl formic acid, methyl benzoyl formate, ethyl benzoylformate, propyl benzoyl formate, 4-hydroxybenzoyl formic acid,4-hydroxyphenyl pyruvic acid, and 2-hydroxyphenyl pyruvic acid.
 9. Themethod of claim 1 wherein said compound is a hydroxydicarboxylic acidhaving the following chemical structural formula:

wherein m=1,2,3,4,5,6,7,8, or 9 n=0 or a numerical number up to 23present as free acid, lactone or salt form, and as optically active orinactive D, L, and meso isomer; hydrogen atom attached to the carbonatom may be substituted by a nonfunctional F, Cl, Br, I, or S atom or alower alkyl or alkoxy saturated or unsaturated radical, having 1 to 9carbon atoms.
 10. The method of claim 9 wherein said hydroxydicarboxylicacid is a member selected from the group consisted of2-hydroxypropanedioic acid; 2-hydroxybutanedioic acid; erythraric acid;threaric acid; arabiraric acid; ribaric acid; xylaric acid; lyxaricacid; glucaric acid; galactaric acid; mannaric acid; gularic acid;allaric acid; altraric acid; idaric acid; talaric acid;2-hydroxy-2-methylbutanedioic acid.
 11. The method of claim 9 whereinsaid hydroxydicarboxylic acid is a member derived from an amino acid bysubstituting the amino group with a hydroxy group.
 12. The method ofclaim 9 wherein said lactone is an intermolecular or intra molecularlactone including saccharic acid, 1,4-lactone.
 13. A method forenhancing the therapeutic effect of a composition comprising a cosmeticor pharmaceutical agent in a pharmaceutically acceptable vehicle fortopical application to the skin of humans or animals comprising:admixing with said composition an enhancing effective amount of at leastone member selected from the group consisting of Hydroxycarboxylic acidof R(OH)_(m)(COOH)_(n) Wherein m,n=1,2,3,4,5,6,7,8 or 9 R=H, alkyl,aralkyl or aryl group of saturated or unsaturated, straight or branchedchain or cyclic form, having 1 to 25 carbon atoms. citric acid,isocitric acid, agaricic acid, quinic acid, citramalic acid, glucuronicacid, glucuronolactone, galacturonic acid, galacturonolactone, uronicacids, uronolactones, ascorbic acid, dihydroascorbic acid,dihydroxytartaric acid, 1-hydroxy-1-cyclopropanecarboxylic acid,2-hydroxyhexanedial, 5-hydroxylysine, 3-hydroxy-2-aminopentanoic acid,4-hydroxy-3-pentenoic acid, tropic acid, 4-hydroxy-2, 2-diphenylbutanoicacid, and 3-hydroxy-3-methylglutaric acid and ester, lactone or saltforms thereof, and as an optically active or inactive D, L, DL or mesoisomer; the hydrogen atom attached to the carbon atom may be substitutedby a nonfunctional F, Cl, Br, I or S atom or a lower alkyl or alkoxysaturated or unsaturated radical having
 1. to 9 carbon atoms.
 14. Themethod of claim 13 wherein the lactone is an inter or intramolecularlactone.
 15. A therapeutic composition effective against skin conditionsand disorders comprising an effective amount of at least one compoundselected from the group consisting of: Citramalic acid, Diphenyl2-hydroxyacetic acid (benzilic acid), 2-phenyl 3-hydroxypropanoic acid(tropic acid), aleuritic acid, ribonic acid, ribonoloactone,2,3,4-trihydroxybutanoic -acid, 2,3,4,5-tetrahydroxypentanoic acid,2,3,4,5,6-pentahydroxyhexanoic acid, 2-hydroxylauric acid,2,3,4,5,6,7-hexahydrokyheptanoic acid, 4-hydroxymandelic acid,4-chloromandelic acid, 2-hydroxy-3-methylbutanoic acid,2-hydroxy-4-methylpentanoic acid, 3-hydroxy-4-methoxymandelic acid,4-hydroxy-3-methoxymandelic acid, 3-(3-hyroxphenyl) lactic acid,3-(4-hydroxyphenyl) lactic acid, hexahydromandelic acid,3-hydroxy-3-methylpentanoic acid, 1-hydroxy-1-cyclopropane carboxylicacid, 4-hydroxybutanoic acid, 2-hydroxyhexanoic acid, 5-hydroxylauricacid, 12-hydroxylauric acid, 10-hydroxydecanoic acid,16-hydroxyhexadecanoic acid, 4-hydroxydecanoic acid, 5-hydroxydecanoicacid, and 4-hydroxy-2, 2-diphenylbutanoic acid. as a free acid or saltform in a pharmaceutically or cosmetically acceptable vehicle.
 16. Thecomposition of claim 15 wherein said skin conditions and disordersinclude dry skin, dandruff, keratoses, age spots, warts, acne, oilyskin, eczema, psoriasis, wrinkles, inflammatory and pruritic skin, anddisturbed keratinization.
 17. A method for alleviating the symptoms ofskin conditions and disorders comprising the topical application of atherapeutic effective amount of at least one compound selected from thegroup consisting of: Diphenyl 2-hydroxyacetic acid (benzilic acid),2-phenyl 3-hydroxypropanoic acid (tropic acid), aleuritic acid, ribonicacid, ribonoloactone, 2,3,4-trihydroxybutanoic acid,2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoic acid,2-hydroxylauric acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid,4-hydroxymandelic acid, 4-chloromandelic acid,2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid,3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid,3-(2-hydroxphenyl) lactic acid, citramalic acid, 3-(4-hydroxyphenyl)lactic acid, hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid,1-hydroxy-1-cyclopropane carboxylic acid, 4-hydroxybutanoic acid,2-hydroxyhexanoic acid, hydroxylauric acid, 12-hydroxylauric acid,10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxydecanoicacid, 5-hydroxydecanoic acid, and 4-hydroxy-2, 2-diphenylbutanoic acidas a free acid or salt form in a pharmaceutically or cosmeticallyacceptable vehicle.
 18. The method of claim 17 wherein said skinconditions and disorders include dry skin, dandruff, keratoses, agespots, wrinkles, warts, acne, oily skin, eczema, psoriasis, inflammatoryand pruritic skin, and disturbed keratinization.
 19. An enhancedtherapeutic composition effective against skin conditions and disorderscomprising an effective amount of at least one member selected from thegroup consisting of hydroquinone and hydroquinone monoether includingmonomethyl and monobenzyl ether and an enhancing effective amount of atleast one member selected from the group consisting of hydroxycarboxylicacids and related ketocarboxylic acids, and ester, lactone or salt formthereof, in a pharmaceutically acceptable vehicle for topicalapplication to skin of human or animal body.
 20. The composition ofclaim 19 wherein said skin conditions and disorders include keratoses,age spots, wrinkles, brownish spots, melasma, lentigines and otherpigmented skin spots.
 21. The composition of claim 19 wherein said acidsand related compounds include glycolic acid, benzilic acid, tropic acid,lactic acid, malic acid, citric acid, isocitric acid, citramalic acid,tartronic acid, tartaric acid, gluconic acid, galactonic acid, alphahydroxyisobutyric acid, phenyllactic acid, mandelic acid, atrolacticacid, gluconolactone, galactonolactone, ribonic acid, ribonolactone,pantoic acid, pantolactone, pantothenic acid, alpha hydroxybutyric acid,Beta hydroxybutyric acid, quinic acid, pyruvic acid, phenyl pyruvicacid, methyl pyruvate, ethyl pyruvate, ascorbic acid, benzoyl formicacid,. methyl benzoyl formate, and ethyl benzoyl formate.
 22. A methodfor enhancing therapeutic effects a composition of hydroquinone or itsmonoether derivative in a pharmaceutically acceptable vehicle comprisingadmixing therewith an enhancing effective amount of at least one memberselected from the group consisting of hydroxycarboxylic acids andrelated ketocarboxylic acids, and ester, lactone or salt forms thereof.23. The method of claim 22 wherein said hydroxyacids and relatedcompounds include glycolic acid, benzilic acid, tropic acid, lacticacid, malic acid, citric acid, isocitric acid, citramalic acid,tartronic acid, tartaric acid, gluconic acid, galactonic acid, alphahydroxyisobutyric acid, phenyllactic acids mandelic acid, atrolacticacid, gluconolactone, galactonolactone, ribonic acid, ribonolactone,pantoic acid, pantolactone, pantothenic acid, alpha hydroxybutyric acid,beta hydroxybutyric acid, quinic acid, pyruvic acid, phenyl pyruvicacid, methyl pyruvate, ethyl pyruvate, ascorbic acid, benzoyl formicacid, methyl benzoyl formate, ethyl benzoyl formate.
 24. A method forpreventing hair loss and/or enhancing hair growth comprising the topicalapplication of a combination composition consisting of minoxidil ordipyridamole and an enhancing effective amount of at least one memberselected from the group consisting of hydroxycarboxylic acids andrelated ketocarboxylic acids, and ester, lactone or salt forms thereofpharmaceutically acceptable vehicle for topical application to skin ofhuman or animal body.
 25. The method of claim 24 wherein saidhydroxycarboxylic acid or related compound is a member selected from thegroup consisted of lactic acid, glycolic acid, glucuronic acid,gluconolactone, gluconic acid, 2-methyl 2-hydroxypropanoic acid,mandelic acid, tropical acid, benzilic acid, malic acid, tartaric acid,citric acid, tartronic acid, pyruvic acid, methyl pyruvate, ethylpyruvate, saccharic acid, isocitric acid, agaricic acid, citramalicacid, aleuritic acid, mucic acid, galaturonic acid, phenyllactic acid,benzoylformic acid, atrolactic acid, galactonic acid, ascorbic acid,dihydroascorbic acid, pantoyllactone, gulonic acid, gulonolactone,pantoic acid, ribonic acid, ribonolactone, 3-hydroxybutanoic acid,4-hydroxymandelic acid,-2-hydroxy-3-methylbutanoic acid,3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid,4-chloromandelic acid, 2-hydroxy-4-methylpentanoic acid,2-hydroxy-2-methylbutanoic acid, 3-(2-hydroxyphenyl) lactic acid,3-(4-hydroxyphenyl) lactic acid and hexahydromandelic acid.
 26. Atherapeutic composition useful in preventing hairloss and/or enhancinghairgrowth comprising a combination composition consisting of aneffective amount of minoxidil or dipyridamole and an enhancing effectiveamount of at least one member selected from the group consisting ofhydroxycarboxylic acids and related ketocarboxylic acids, and ester,lactone or salt forms thereof pharmaceutically acceptable vehicle fortopical application to skin of human or animal body.
 27. The compositionof claim 26 wherein said hydroxycarboxylic acid or related compound is amember selected from the group consisted of lactic acid, glycolic acid,glucuronic acid, gluconolactone, gluconic acid, 2-methyl2-hydroxypropanoic acid, mandelic acid, tropic acid, benzilic acid,malic acid, tartaric acid, citric acid, tartronic acid, pyruvic acid,methyl pyruvate, ethyl pyruvate, saccharic acid, isocitric acid,agaricic acid, citramalic acid, aleuritic acid, mucic acid, galacturonicacid, phenyllactic acid, benzoylformic acid, atrolactic acid, galactonicacid, ascorbic acid, dihydroascorbic acid, pantoyllactone, gulonic acid,gulonolactone, pantoic acid, ribonic acid, ribonolactone,3-hydroxybutanoic acid, 4-hydroxymandelic acid,2-hydroxy-3-methylbutanoic acid, 3-hydroxy-4-methoxymandelic acid,4-hydroxy-3-methoxymandelic acid, 4-chloromandelic acid,2-hydroxy-4-methylpentanoic acid, 2-hydroxy-2-methylbutanoic acid,3-(2-hydroxyphenyl) lactic acid, 3-(4-hydroxyphenyl) lactic acid andhexahydromandelic acid.
 28. A therapeutic composition useful inpreventing hairloss and/or enhancing hair growth comprising an effectiveamount of dipyridamole in a pharmaceutically acceptable vehicle fortopical application to skin of human or animal body.
 29. A method forpreventing hairloss and/or enhancing hair growth comprising the topicalapplication of a composition consisting of dipyridamole in apharmaceutically acceptable vehicle for topical application to skin ofhuman or animal body.
 30. A prophylactic and therapeutic compositioneffective against acne and for oily skin and as skin cleanser comprisingan effective amount of benzilic acid in a pharmaceutically acceptablevehicle for topical application to skin of human or animal body.
 31. Amethod for preventing as well as treating acne or for oily skin as skincleanser comprising the topical application to involved skin of acomposition containing an effective amount of benzilic acid in apharmaceutically acceptable vehicle for topical application to skin ofhuman or animal body.
 32. A method for preventing as well as treatingwrinkles or skin changes associated with aging of skin comprising thetopical application to involved skin of a composition containing atherapeutic effective amount of at least one member selected from thegroup consisted of hydroxycarboxylic acids and related ketocarboxylicacids, and ester, lactone or salt forms thereof.
 33. The method of claim32 wherein said hydroxycarboxylic acids and related compounds include2-Hydroxyacetic acid; 2-hydroxypropanoic acid; 2-methyl2-hydroxypropanoic acid; 2-hydroxybutanoic acid; phenyl 2-hydroxyaceticacid; phenyl 2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyaceticacid; 2,3-dihydroxypropanoic acid; 2,3,4-trihydroxybutanoic acid,2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoic acid,2-hydroxydodecanoic acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid,diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid; 4-chloromandelicacid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid; 2-hydroxyhexanoicacid; 5-hydroxydodecanoic acid, 12-hydroxydodecanoic acid,10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid,2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid;3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxyphenyl) lactic acid:3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid; 2-Hydroxypropanedioic acid;2-hydroxybutanedioic acid; erythraric acid; threaric acid; arabiraricacid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid;galactaric acid; mannaric acid; gularic acid; allaric acid; altraricacid; idaric acid; talaric acid; 2-hydroxy-2-methylbutanedioic acid;Citric acid, isocitric acid, agaricic acid, quinic acid, glucuronicacid, glucuronolactone, galacturonic acid, galacturonolactone, uronicacids, uronolactones, ascorbic acid, dihydroascorbic acid,dihydroxytartaric acid, tropic acid, ribonolactone, gluconolactone,galactonolactone, gulonolactone, mannonolactone, ribonic acid, gluconicacid, citramalic acid; Pyruvic acid, hydroxypyruvic acid, hydroxypyruvicacid phosphate, methyl pyruvate, ethyl pyruvate, propyl pyruvate,isopropyl pyruvate; phenyl pyruvic acid, methyl phenyl pyruvate, ethylphenyl pyruvate, propyl phenyl pyruvate; formyl formic acid, methylformyl formate, ethyl formyl formate, propyl formyl formate, benzoylformic acid, methyl benzoyl formate, ethyl benzoyl formate, propylbenzoyl formate, 4-hydroxybenzoyl formic acid, 4-hydroxyphenyl pyruvicacid, 2-hydroxyphenyl pyruvic acid.
 34. A prophylactic and therapeuticcompositions comprising an effective amount of at least one memberselected from the group consisted of hydroxycarboxylic acids and relatedketocarboxylic acids, and ester, lactone or salt forms thereof in apharmaceutically acceptable vehicle for topical treatment of skinwrinkles or skin changes associated with aging.
 35. The composition ofclaim 34 wherein said hydroxycarboxylic acids and related compoundsinclude 2-Hydroxyacetic acid; 2-hydroxypropanoic acid; 2-methyl2-hydroxypropanoic acid; 2-hydroxybutanoic acid; phenyl 2-hydroxyaceticacid; phenyl 2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyaceticacid; 2,3-dihydroxypropanoic acid; 2,3,4-trihydroxybutanoic acid,2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoic acid,2-hydroxydodecanoic acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid,diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid; 4-chloromandelicacid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid; 2-hydroxyhexanoicacid; 5-hydroxydodecanoic acid, 12-hydroxydodecanoic acid,10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid,2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid;3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxyphenyl) lactic acid;3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid; 2-Hydroxypropanedioic acid;2-hydroxybutanedioic acid; erythraric acid; threaric acid; arabiraricacid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid;galactaric acid; mannaric acid; gularic acid; allaric acid; altraricacid; idaric acid; talaric acid; 2-hydroxy-2-methylbutanedioic acid;Citric acid, isocitric acid, agaricic acid, quinic acid, glucuronicacid, glucuronolactone, galacturonic acid, galacturonolactone, uronicacids, uronolactones, ascorbic acid, dihydroascorbic acid,dihydroxytartaric acid, tropic acid, ribonolactone, gluconolactone,galactonolactone, gulonolactone, mannonolactone, ribonic acid, gluconicacid, citramalic acid; Pyruvic acid, hydroxypyruvic acid, hydroxypyruvicacid phosphate, their esters; methyl pyruvate, ethyl pyruvate, propylpyruvate, isopropyl pyruvate; phenyl pyruvic acid, its esters; methylphenyl pyruvate, ethyl phenyl pyruvate, propyl phenyl pyruvate; formylformic acid, its esters; methyl formyl formate, ethyl formyl formate,propyl formyl formate; benzoyl formic acid, its esters; methyl benzoylformate, ethyl benzoyl formate, propyl benzoyl formate; 4-hydroxybenzoylformic acid, its esters; 4-hydroxyphenyl pyruvic acid, its esters;2-hydroxyphenyl pyruvic acid and its esters.